Abdominal cramping, nausea, diarrhea, and GI bleeding are often reported in long-distance runners. This study set out to determine the effects of prolonged (2-4 hrs) exercise and NSAID ingestion on gastric and intestinal permeability during the first 5 hrs following the 1996 Chicago Marathon. Thirty-four healthy volunteers (20 M, 14 F; ages 30-50) completed the race and ingested the test solution (5 g sucrose, 5 g lactulose, 2 g rhamnose, in 40 ml water) within 10-15 min. The urinary excretion ratio of lactulose/rhamnose was used to assess small intestine permeability; sucrose excretion was used to evaluate gastric impairment. There were no significant differences for mean training mileage, postrace rectal temperature, and percent dehydration between runners who ingested NSAIDs and those who did not. In all, 75% of subjects reported aspirin or ibuprofen ingestion before or during the race. Runners who ingested ibuprofen had significant elevations in urinary lactulose excretion and lactulose/rhamnose ratio, whereas those who ingested aspirin or who did not ingest either NSAID had no significant differences in urinary excretion of lactulose, rhamnose, sucrose, or lactulose/rhamnose ratio compared to resting controls. Thirteen of the 26 NSAID users and 4 of the 8 non-users reported GI symptoms. It is concluded that (a) ibuprofen but not aspirin ingestion during prolonged exercise may increase gastrointestinal permeability and lead to GI symptoms, and (b) prolonged exercise alone can produce GI symptoms.